Letters
Author Affiliations: Independent data scientist (self-employed), Seattle, Washington (Harding); Department of Physics, Harvard University, Cambridge, Massachusetts (Pompei, Wilson). Corresponding Author: Richard Wilson, DPhil, Harvard University Department of Physics, 17 Oxford St, Cambridge, MA 02138 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Mr Harding reported receiving funding from Exergen Corp for work on this letter; previous consulting for Janssen Pharmaceuticals, Johnson & Johnson Pharmaceuticals, Lifeline Screening, Novartis Pharmaceuticals, and Innovative Science Solutions; previous employment by Innovative Science Solutions; and receiving payment for manuscript editing from Cactus Global. Neither the consulting, employment, or editing pertained to the topics of this letter. Dr Pompei reported being CEO of Exergen Corp, a manufacturer of noninvasive thermometry devices. No other disclosures were reported. 1. Silber JH, Rosenbaum PR, Clark AS, et al. Characteristics associated with differences in survival among black and white women with breast cancer. JAMA. 2013;310(4):389-397. 2. Esserman LJ, Thompson IM Jr, Reid B. Overdiagnosis and overtreatment in cancer: an opportunity for improvement. JAMA. 2013;310(8):797-798. 3. Marmot MG, Altman DG, Cameron DA, Dewar JA, Thompson SG, Wilcox M. The benefits and harms of breast cancer screening: an independent review. Br J Cancer. 2013;108(11):2205-2240. 4. Bleyer A, Welch HG. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med. 2012;367(21):1998-2005. 5. Albain KS, Unger JM, Crowley JJ, Coltman CA Jr, Hershman DL. Racial disparities in cancer survival among randomized clinical trials patients of the Southwest Oncology Group. J Natl Cancer Inst. 2009;101(14):984-992.
In Reply Our study examined all 7375 black women older than 65 years diagnosed with breast cancer between 1991 and 2005 in the Surveillance, Epidemiology, and End Results database. Although Mr Harding and colleagues quote various numbers to illustrate the potential effect of overdiagnosis on racial disparities in breast cancer survival, these are hypothetical. We matched patients for cancer stage and many other characteristics, in which stage was determined from the database based on chart review. That chart review included information from biopsy and postsurgical pathology. On this basis, patients with ductal carcinoma in situ (DCIS) were excluded from our data set. Although overdiagnosis may lead to unnecessary biopsies or unneeded treatment of patients with DCIS, neither of these possibilities are relevant to our study. Harding and colleagues cite an Editorial by Esserman et al1 that referred to the problematic diagnosis of DCIS when estimating cancer survival and suggest that premalignant conditions “(eg, ductal carcinoma in situ or high-grade prostatic intraepithelial neoplasia) should not be labeled as cancers or neoplasia, nor should the word ‘cancer’ be in the name.” Harding and colleagues suggest an additional analysis that takes account of breast cancer screening. As suggested, in each of our 3 matched black and white patient comparisons, we adjusted for the indicator of mammographic screening and obtained results qualitatively similar to those reported in Table 2 of our article. Initially, black and white patients had different survival prospects, but the majority of this difference was removed by comparing black and white women with similar cancers (eg, stage, size, grade, estrogenreceptor status) and similar comorbidities (eg, congestive heart failure, diabetes). Black women received somewhat inferior
cancer treatment, but this explained only a small portion of the disparity in survival. These results are not changed by adjustment for screening. The adjustment used the Cox proportional hazards model for paired survival data as used several times for other analyses in our study (eg, the adjustment for income). After adjustment for screening, the black-white hazard ratio was 1.41 (95% CI, 1.32-1.50) in the demographic match, 1.11 (95% CI, 1.04-1.18) in the presentation match, and 1.05 (95% CI, 0.98-1.11) in the treatment match. Consistent with Table 2, there is a large initial disparity that is mostly explained by differences in presentation, not differences in treatment. Discussions of our study by Harding and colleagues and others2 have confused 2 different questions. First, does treatment matter for survival? Second, do disparities in treatment explain most of the disparity in survival? To explain the blackwhite disparity in survival following a diagnosis of breast cancer, treatment would have to matter for survival and also be substantially different for black and white patients with similar disease. Jeffrey H. Silber, MD, PhD Paul R. Rosenbaum, PhD Kevin R. Fox, MD Author Affiliations: Center for Outcomes Research, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania (Silber); Department of Statistics, University of Pennsylvania, Philadelphia (Rosenbaum); Leonard and Madlyn Abramson Cancer Center, University of Pennsylvania, Philadelphia (Fox). Corresponding Author: Jeffrey H. Silber, MD, PhD, Children’s Hospital of Philadelphia, 3535 Market St, Ste 1029, Philadelphia, PA 19104 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Esserman LJ, Thompson IM Jr, Reid B. Overdiagnosis and overtreatment in cancer: an opportunity for improvement. JAMA. 2013;310(8):797-798. 2. Mandelblatt JS, Sheppard VB, Neugut AI. Black-white differences in breast cancer outcomes among older Medicare beneficiaries: does systemic treatment matter? JAMA. 2013;310(4):376-377.
Therapy for Posttraumatic Stress and Alcohol Dependence To the Editor In a randomized clinical trial, Dr Foa and colleagues1 examined prolonged exposure psychotherapy for co-occurring posttraumatic stress disorder (PTSD) and alcohol dependence. Prolonged exposure therapy was studied in relation to supportive counseling, use of naltrexone, and a pill placebo. The article provides an example of how the same findings can be interpreted quite differently when considered from a public health perspective. Results of the trial were null for prolonged exposure therapy; it did not show a main effect on substance use disorder or on PTSD compared with supportive counseling. Yet the authors concluded simply that prolonged exposure therapy did not exacerbate substance use disorder. Thirty-five studies of PTSD with substance use disorder, ranging from pilot studies to multisite trials, have shown that treating PTSD in the context of substance use disorder does not worsen either disorder.2
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JAMA December 11, 2013 Volume 310, Number 22
Copyright 2013 American Medical Association. All rights reserved.
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From a public health perspective, the novel finding of the study by Foa and colleagues1 is that supportive counseling, which is a low-cost, easily trainable, and well-tolerated approach, did as well for both PTSD and substance use disorder as prolonged exposure, which is a more expensive, less easily trainable, and less well-tolerated model. Moreover, this is the fourth of 4 randomized clinical trials to show a lack of main effect for PTSD exposure therapy on either PTSD or substance use disorder compared with less emotionally intense therapy at the end of treatment.3-5 Foa and colleagues1 also found low attendance at prolonged exposure therapy sessions, which was also a problem in prior studies.3 Yet they concluded that future research should find ways to increase attendance by patients at prolonged exposure therapy sessions. A public health perspective might suggest instead that prolonged exposure therapy is not a strong option for this population. A decade ago, Foa identified that prolonged exposure therapy is not a first-line treatment for PTSD with substance use disorder.2 The evidence now supports that. Clinicians report that patients with PTSD and substance use disorder are more difficult to treat than patients with only PTSD, for example.2 In sum, prolonged exposure therapy likely works best with less complex patients. There is often a rush to label treatments as evidencebased, and prolonged exposure has been widely identified as such.1,4,5 The study by Foa et al1 speaks to the importance of recognizing that for more challenging patients, a therapy such as supportive counseling may be no less powerful than prolonged exposure, yet more sensitive to public health needs. Lisa M. Najavits, PhD Author Affiliation: Veterans Affairs Boston Healthcare System, Boston, Massachusetts. Corresponding Author: Lisa M. Najavits, PhD, VA Boston Healthcare System, 150 S Huntington Ave, Boston, MA 02130 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported being director of Treatment Innovations, which provides training, consultation, and materials related to psychotherapies. 1. Foa EB, Yusko DA, McLean CP, et al. Concurrent naltrexone and prolonged exposure therapy for patients with comorbid alcohol dependence and PTSD: a randomized clinical trial. JAMA. 2013;310(5):488-495. 2. Najavits LM, Hien DA. Helping vulnerable populations: a comprehensive review of the treatment outcome literature on substance use disorder and PTSD. J Clin Psychol. 2013;69(5):433-479. 3. Mills KL, Teesson M, Back SE, et al. Integrated exposure-based therapy for co-occurring posttraumatic stress disorder and substance dependence: a randomized controlled trial. JAMA. 2012;308(7):690-699. 4. van Dam D, Ehring T, Vedel E, Emmelkamp PM. Trauma-focused treatment for posttraumatic stress disorder combined with CBT for severe substance use disorder: a randomized controlled trial. BMC Psychiatry. 2013;13(1):172. 5. Sannibale C, Teesson M, Creamer M, et al. Randomized controlled trial of cognitive behaviour therapy for comorbid post-traumatic stress disorder and alcohol use disorders. Addiction. 2013;108:1397-1410.
In Reply Dr Najavits states that our findings would be interpreted differently if considered from a public health perspective, noting that results of this trial were null for pro2458
longed exposure therapy. In truth, our results showed that prolonged exposure therapy, especially when combined with naltrexone, significantly reduced alcohol craving and alcohol relapse, findings that are relevant to public health. In addition, a significantly greater proportion of patients who received prolonged exposure therapy (vs those who did not) had minimal PTSD symptoms 6 months after treatment discontinuation. The critique by Najavits dismisses the important finding that delivering prolonged exposure therapy within the first week of detox did not exacerbate alcohol use or craving. There has been a widespread belief that implementing exposure in the early months of fragile sobriety is harmful, a belief that constituted a major barrier to treating PTSD in individuals with alcohol dependence. Our study showed that patients can benefit from unmodified prolonged exposure therapy immediately after detox and while working on sobriety. Thus, prolonged exposure therapy is a strong option for this population. It is true that there was no significant main effect for prolonged exposure therapy combined with counseling vs counseling alone for PTSD during acute treatment. It is also true that other treatments for PTSD and substance abuse, such as seeking safety,1 have not been shown to reduce substance abuse or PTSD symptoms more than education. However, in our study in the long run, supportive counseling was less effective for alcohol abuse and PTSD. Although supportive counseling may be less costly and more easily trainable, from a public health perspective, investments should be made in treatments that promote long-term wellness rather than focusing on shortterm effects. As Najavits correctly points out, a decade ago Foa questioned whether prolonged exposure therapy should be delivered to patients with PTSD and substance use disorder. However, clinical impressions should be submitted to rigorous investigation. Our results demonstrate that Foa’s original view was incorrect because prolonged exposure therapy has been found to be effective in reducing PTSD and minimizing risk of alcohol relapse. The efficacy of prolonged exposure therapy has been established in many studies by independent research groups, including studies with complex populations.2 Therefore, the comment by Najavits that there is a rush to label prolonged exposure therapy as evidence-based is unfounded and potentially harmful to the greater public health because it can discourage the use of an effective treatment for PTSD among patients with alcohol dependence. The results of our study are by no means the final answer to the issue of how best to treat those with both PTSD and alcohol dependence, but we assert that this randomized clinical trial meaningfully informs treatment standards for this debilitated clinical population. Edna B. Foa, PhD Carmen P. McLean, PhD David Yusko, PsyD Author Affiliations: Center for the Treatment and Study of Anxiety, University of Pennsylvania, Philadelphia.
JAMA December 11, 2013 Volume 310, Number 22
Copyright 2013 American Medical Association. All rights reserved.
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Corresponding Author: Edna B. Foa, PhD, University of Pennsylvania Department of Psychiatry, 3535 Market St, Sixth Floor, Philadelphia, PA 19104 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Foa reported receiving research funding from the Department of Defense, Department of Veterans Affairs, and National Institutes of Health; and receiving income from published books on posttraumatic stress disorder treatment. No other disclosures were reported. 1. Hien DA, Wells EA, Jiang H, et al. Multisite randomized trial of behavioral interventions for women with co-occurring PTSD and substance use disorders. J Consult Clin Psychol. 2009;77(4):607-619. 2. McLean CP, Foa EB. Prolonged exposure therapy for post-traumatic stress disorder: a review of evidence and dissemination. Expert Rev Neurother. 2011;11(8):1151-1163.
Drug Postmarketing Studies To the Editor The authors of a research letter1 acknowledged the important role that postmarketing studies play in enhancing the safe and effective use of drugs and recognized the importance of the US Food and Drug Administration (FDA) Amendments Act (FDAAA) of 2007 in authorizing the FDA to require postmarketing safety studies and trials.2 However, Fain and colleagues1 also used annual FDA reports published in the Federal Register to assess the effects of the FDAAA on timely conduct of postmarketing studies and failed to consider certain data supplied in those reports and in other public information. We wish to provide some clarification. The annual reports pertain not only to the status of postmarketing requirements (required under the FDAAA2 or other authorities3), but also to postmarketing commitments, which are mutually agreed upon between the FDA and drug sponsors (without FDAAA authority). The postmarketing requirements and commitments in these reports include the backlog of investigations with an open status4 as of September 27, 2007, which is when the FDAAA was enacted. As required by the FDAAA, the FDA has regularly assessed the status of the backlog and provided updates to the public.4,5 Although Fain and colleagues1 correctly concluded that the total number of fulfilled and delayed postmarketing requirements and commitments increased between 2007 and 2011, they did not acknowledge the effect of the FDA’s review of the backlog on the trends reported over time. The backlog review revealed errors in the status of many postmarketing requirements and commitments. Prior to FDA review, original backlog data reported 64% as pending, 15% as ongoing, and 7% as delayed, whereas after FDA review, 14% were pending, 14% ongoing, 36% submitted, and 15% were delayed. Correction of these errors, combined with a dedicated effort by the FDA to review submitted reports for postmarketing requirements and commitments, contributed significantly to the trends reported by the authors. It is also important to understand that pending status does not reflect a delay. Pending investigations are instead proceeding according to the schedule set by the FDA, even if the study has not yet started. The FDA makes concerted efforts to determine the status of postmarketing requirements regularly, assess reasons for any delay, and provide updates to the public. Nearly all
FDAAA postmarketing requirements (99% in 2011) are progressing according to the original schedules set by the FDA. Mwango Kashoki, MD, MPH Cathryn Lee, BSN, MSN, CRNP John Jenkins, MD Author Affiliations: Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland. Corresponding Author: Mwango Kashoki, MD, MPH, Food and Drug Administration, 10903 New Hampshire Ave, WO 22, Room 6464, Silver Spring, MD 20993 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Fain K, Daubresse M, Alexander GC. The Food and Drug Administration Amendments Act and postmarketing commitments. JAMA. 2013;310(2): 202-204. 2. Title IX, subtitle A, §901 of Food and Drug Administration Amendments Act added to the Foods, Drug, and Cosmetic Act (§505[o], 21 USC 355[o]). 3. US Code of Federal Regulations, 21 CFR 314.55(b), 314.510, 314.610(b)(1), 601.27(b), 601.41, and 601.91(b)(1). 4. US Food and Drug Administration. Independent evaluation of FDA’s Prescription Drug User Fee Act—evaluations and initiatives: CDER technical support and analysis. http://www.fda.gov /downloads/Drugs/GuidanceComplianceRegulatoryInformation /Post-marketingPhaseIVCommitments/UCM181135.pdf. Accessed August 7, 2013. 5. US Food and Drug Administration. Report on the review of the backlog of postmarketing requirements and commitments by FDA. http://www .fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation /Post-marketingPhaseIVCommitments/UCM291522.pdf. Accessed August 7, 2013.
In Reply Dr Kashoki and colleagues provide helpful insight about progress made in decreasing the backlog of postmarketing studies from September 2007, when the FDAAA was enacted. Despite this, our research aim was broader: to examine the annual number of postmarketing studies, both required and voluntary, in each status category and the trends since the law’s enactment. The initial backlog of studies is an important part of the picture. However, since September 2007, many new postmarketing studies have been required by the FDA or voluntarily established. The data in the Agency’s Federal Register notices, upon which our analysis relied, include both the backlogged and new studies.1 The revised data cited by the authors, and described in a Congressional report,2 reflect the updated status of the initial backlog of studies as of February 2009, approximately 17 months after FDAAA enactment, but these data do not reflect the status of all postmarketing studies in 2009, or change either our main findings or their substantive interpretation. The estimates by Kashoki and colleagues that approximately 15% of these backlogged studies were delayed in 2009, as well as the Agency’s estimates that 14% of backlogged studies were delayed in 2010,3 are consistent with our estimates that approximately 1 in 8 of all postmarketing studies (241/1781) in 2011 were delayed. This appears to agree with our conclusions about the yearly numbers and trends, particularly that both the number of fulfilled and delayed studies increased during this period.
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Author Affiliations: Independent data scientist (self-employed), Seattle, Washington (Harding); Department of Physics, Harvard University, Cambridge, Massachusetts (Pompei, Wilson). Corresponding Author: Richard Wilson, DPhil, Harvard University Department of Physics, 17 Oxford St, Cambridge, MA 02138 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Mr Harding reported receiving funding from Exergen Corp for work on this letter; previous consulting for Janssen Pharmaceuticals, Johnson & Johnson Pharmaceuticals, Lifeline Screening, Novartis Pharmaceuticals, and Innovative Science Solutions; previous employment by Innovative Science Solutions; and receiving payment for manuscript editing from Cactus Global. Neither the consulting, employment, or editing pertained to the topics of this letter. Dr Pompei reported being CEO of Exergen Corp, a manufacturer of noninvasive thermometry devices. No other disclosures were reported. 1. Silber JH, Rosenbaum PR, Clark AS, et al. Characteristics associated with differences in survival among black and white women with breast cancer. JAMA. 2013;310(4):389-397. 2. Esserman LJ, Thompson IM Jr, Reid B. Overdiagnosis and overtreatment in cancer: an opportunity for improvement. JAMA. 2013;310(8):797-798. 3. Marmot MG, Altman DG, Cameron DA, Dewar JA, Thompson SG, Wilcox M. The benefits and harms of breast cancer screening: an independent review. Br J Cancer. 2013;108(11):2205-2240. 4. Bleyer A, Welch HG. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med. 2012;367(21):1998-2005. 5. Albain KS, Unger JM, Crowley JJ, Coltman CA Jr, Hershman DL. Racial disparities in cancer survival among randomized clinical trials patients of the Southwest Oncology Group. J Natl Cancer Inst. 2009;101(14):984-992.
In Reply Our study examined all 7375 black women older than 65 years diagnosed with breast cancer between 1991 and 2005 in the Surveillance, Epidemiology, and End Results database. Although Mr Harding and colleagues quote various numbers to illustrate the potential effect of overdiagnosis on racial disparities in breast cancer survival, these are hypothetical. We matched patients for cancer stage and many other characteristics, in which stage was determined from the database based on chart review. That chart review included information from biopsy and postsurgical pathology. On this basis, patients with ductal carcinoma in situ (DCIS) were excluded from our data set. Although overdiagnosis may lead to unnecessary biopsies or unneeded treatment of patients with DCIS, neither of these possibilities are relevant to our study. Harding and colleagues cite an Editorial by Esserman et al1 that referred to the problematic diagnosis of DCIS when estimating cancer survival and suggest that premalignant conditions “(eg, ductal carcinoma in situ or high-grade prostatic intraepithelial neoplasia) should not be labeled as cancers or neoplasia, nor should the word ‘cancer’ be in the name.” Harding and colleagues suggest an additional analysis that takes account of breast cancer screening. As suggested, in each of our 3 matched black and white patient comparisons, we adjusted for the indicator of mammographic screening and obtained results qualitatively similar to those reported in Table 2 of our article. Initially, black and white patients had different survival prospects, but the majority of this difference was removed by comparing black and white women with similar cancers (eg, stage, size, grade, estrogenreceptor status) and similar comorbidities (eg, congestive heart failure, diabetes). Black women received somewhat inferior
cancer treatment, but this explained only a small portion of the disparity in survival. These results are not changed by adjustment for screening. The adjustment used the Cox proportional hazards model for paired survival data as used several times for other analyses in our study (eg, the adjustment for income). After adjustment for screening, the black-white hazard ratio was 1.41 (95% CI, 1.32-1.50) in the demographic match, 1.11 (95% CI, 1.04-1.18) in the presentation match, and 1.05 (95% CI, 0.98-1.11) in the treatment match. Consistent with Table 2, there is a large initial disparity that is mostly explained by differences in presentation, not differences in treatment. Discussions of our study by Harding and colleagues and others2 have confused 2 different questions. First, does treatment matter for survival? Second, do disparities in treatment explain most of the disparity in survival? To explain the blackwhite disparity in survival following a diagnosis of breast cancer, treatment would have to matter for survival and also be substantially different for black and white patients with similar disease. Jeffrey H. Silber, MD, PhD Paul R. Rosenbaum, PhD Kevin R. Fox, MD Author Affiliations: Center for Outcomes Research, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania (Silber); Department of Statistics, University of Pennsylvania, Philadelphia (Rosenbaum); Leonard and Madlyn Abramson Cancer Center, University of Pennsylvania, Philadelphia (Fox). Corresponding Author: Jeffrey H. Silber, MD, PhD, Children’s Hospital of Philadelphia, 3535 Market St, Ste 1029, Philadelphia, PA 19104 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Esserman LJ, Thompson IM Jr, Reid B. Overdiagnosis and overtreatment in cancer: an opportunity for improvement. JAMA. 2013;310(8):797-798. 2. Mandelblatt JS, Sheppard VB, Neugut AI. Black-white differences in breast cancer outcomes among older Medicare beneficiaries: does systemic treatment matter? JAMA. 2013;310(4):376-377.
Therapy for Posttraumatic Stress and Alcohol Dependence To the Editor In a randomized clinical trial, Dr Foa and colleagues1 examined prolonged exposure psychotherapy for co-occurring posttraumatic stress disorder (PTSD) and alcohol dependence. Prolonged exposure therapy was studied in relation to supportive counseling, use of naltrexone, and a pill placebo. The article provides an example of how the same findings can be interpreted quite differently when considered from a public health perspective. Results of the trial were null for prolonged exposure therapy; it did not show a main effect on substance use disorder or on PTSD compared with supportive counseling. Yet the authors concluded simply that prolonged exposure therapy did not exacerbate substance use disorder. Thirty-five studies of PTSD with substance use disorder, ranging from pilot studies to multisite trials, have shown that treating PTSD in the context of substance use disorder does not worsen either disorder.2
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JAMA December 11, 2013 Volume 310, Number 22
Copyright 2013 American Medical Association. All rights reserved.
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From a public health perspective, the novel finding of the study by Foa and colleagues1 is that supportive counseling, which is a low-cost, easily trainable, and well-tolerated approach, did as well for both PTSD and substance use disorder as prolonged exposure, which is a more expensive, less easily trainable, and less well-tolerated model. Moreover, this is the fourth of 4 randomized clinical trials to show a lack of main effect for PTSD exposure therapy on either PTSD or substance use disorder compared with less emotionally intense therapy at the end of treatment.3-5 Foa and colleagues1 also found low attendance at prolonged exposure therapy sessions, which was also a problem in prior studies.3 Yet they concluded that future research should find ways to increase attendance by patients at prolonged exposure therapy sessions. A public health perspective might suggest instead that prolonged exposure therapy is not a strong option for this population. A decade ago, Foa identified that prolonged exposure therapy is not a first-line treatment for PTSD with substance use disorder.2 The evidence now supports that. Clinicians report that patients with PTSD and substance use disorder are more difficult to treat than patients with only PTSD, for example.2 In sum, prolonged exposure therapy likely works best with less complex patients. There is often a rush to label treatments as evidencebased, and prolonged exposure has been widely identified as such.1,4,5 The study by Foa et al1 speaks to the importance of recognizing that for more challenging patients, a therapy such as supportive counseling may be no less powerful than prolonged exposure, yet more sensitive to public health needs. Lisa M. Najavits, PhD Author Affiliation: Veterans Affairs Boston Healthcare System, Boston, Massachusetts. Corresponding Author: Lisa M. Najavits, PhD, VA Boston Healthcare System, 150 S Huntington Ave, Boston, MA 02130 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported being director of Treatment Innovations, which provides training, consultation, and materials related to psychotherapies. 1. Foa EB, Yusko DA, McLean CP, et al. Concurrent naltrexone and prolonged exposure therapy for patients with comorbid alcohol dependence and PTSD: a randomized clinical trial. JAMA. 2013;310(5):488-495. 2. Najavits LM, Hien DA. Helping vulnerable populations: a comprehensive review of the treatment outcome literature on substance use disorder and PTSD. J Clin Psychol. 2013;69(5):433-479. 3. Mills KL, Teesson M, Back SE, et al. Integrated exposure-based therapy for co-occurring posttraumatic stress disorder and substance dependence: a randomized controlled trial. JAMA. 2012;308(7):690-699. 4. van Dam D, Ehring T, Vedel E, Emmelkamp PM. Trauma-focused treatment for posttraumatic stress disorder combined with CBT for severe substance use disorder: a randomized controlled trial. BMC Psychiatry. 2013;13(1):172. 5. Sannibale C, Teesson M, Creamer M, et al. Randomized controlled trial of cognitive behaviour therapy for comorbid post-traumatic stress disorder and alcohol use disorders. Addiction. 2013;108:1397-1410.
In Reply Dr Najavits states that our findings would be interpreted differently if considered from a public health perspective, noting that results of this trial were null for pro2458
longed exposure therapy. In truth, our results showed that prolonged exposure therapy, especially when combined with naltrexone, significantly reduced alcohol craving and alcohol relapse, findings that are relevant to public health. In addition, a significantly greater proportion of patients who received prolonged exposure therapy (vs those who did not) had minimal PTSD symptoms 6 months after treatment discontinuation. The critique by Najavits dismisses the important finding that delivering prolonged exposure therapy within the first week of detox did not exacerbate alcohol use or craving. There has been a widespread belief that implementing exposure in the early months of fragile sobriety is harmful, a belief that constituted a major barrier to treating PTSD in individuals with alcohol dependence. Our study showed that patients can benefit from unmodified prolonged exposure therapy immediately after detox and while working on sobriety. Thus, prolonged exposure therapy is a strong option for this population. It is true that there was no significant main effect for prolonged exposure therapy combined with counseling vs counseling alone for PTSD during acute treatment. It is also true that other treatments for PTSD and substance abuse, such as seeking safety,1 have not been shown to reduce substance abuse or PTSD symptoms more than education. However, in our study in the long run, supportive counseling was less effective for alcohol abuse and PTSD. Although supportive counseling may be less costly and more easily trainable, from a public health perspective, investments should be made in treatments that promote long-term wellness rather than focusing on shortterm effects. As Najavits correctly points out, a decade ago Foa questioned whether prolonged exposure therapy should be delivered to patients with PTSD and substance use disorder. However, clinical impressions should be submitted to rigorous investigation. Our results demonstrate that Foa’s original view was incorrect because prolonged exposure therapy has been found to be effective in reducing PTSD and minimizing risk of alcohol relapse. The efficacy of prolonged exposure therapy has been established in many studies by independent research groups, including studies with complex populations.2 Therefore, the comment by Najavits that there is a rush to label prolonged exposure therapy as evidence-based is unfounded and potentially harmful to the greater public health because it can discourage the use of an effective treatment for PTSD among patients with alcohol dependence. The results of our study are by no means the final answer to the issue of how best to treat those with both PTSD and alcohol dependence, but we assert that this randomized clinical trial meaningfully informs treatment standards for this debilitated clinical population. Edna B. Foa, PhD Carmen P. McLean, PhD David Yusko, PsyD Author Affiliations: Center for the Treatment and Study of Anxiety, University of Pennsylvania, Philadelphia.
JAMA December 11, 2013 Volume 310, Number 22
Copyright 2013 American Medical Association. All rights reserved.
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Corresponding Author: Edna B. Foa, PhD, University of Pennsylvania Department of Psychiatry, 3535 Market St, Sixth Floor, Philadelphia, PA 19104 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Foa reported receiving research funding from the Department of Defense, Department of Veterans Affairs, and National Institutes of Health; and receiving income from published books on posttraumatic stress disorder treatment. No other disclosures were reported. 1. Hien DA, Wells EA, Jiang H, et al. Multisite randomized trial of behavioral interventions for women with co-occurring PTSD and substance use disorders. J Consult Clin Psychol. 2009;77(4):607-619. 2. McLean CP, Foa EB. Prolonged exposure therapy for post-traumatic stress disorder: a review of evidence and dissemination. Expert Rev Neurother. 2011;11(8):1151-1163.
Drug Postmarketing Studies To the Editor The authors of a research letter1 acknowledged the important role that postmarketing studies play in enhancing the safe and effective use of drugs and recognized the importance of the US Food and Drug Administration (FDA) Amendments Act (FDAAA) of 2007 in authorizing the FDA to require postmarketing safety studies and trials.2 However, Fain and colleagues1 also used annual FDA reports published in the Federal Register to assess the effects of the FDAAA on timely conduct of postmarketing studies and failed to consider certain data supplied in those reports and in other public information. We wish to provide some clarification. The annual reports pertain not only to the status of postmarketing requirements (required under the FDAAA2 or other authorities3), but also to postmarketing commitments, which are mutually agreed upon between the FDA and drug sponsors (without FDAAA authority). The postmarketing requirements and commitments in these reports include the backlog of investigations with an open status4 as of September 27, 2007, which is when the FDAAA was enacted. As required by the FDAAA, the FDA has regularly assessed the status of the backlog and provided updates to the public.4,5 Although Fain and colleagues1 correctly concluded that the total number of fulfilled and delayed postmarketing requirements and commitments increased between 2007 and 2011, they did not acknowledge the effect of the FDA’s review of the backlog on the trends reported over time. The backlog review revealed errors in the status of many postmarketing requirements and commitments. Prior to FDA review, original backlog data reported 64% as pending, 15% as ongoing, and 7% as delayed, whereas after FDA review, 14% were pending, 14% ongoing, 36% submitted, and 15% were delayed. Correction of these errors, combined with a dedicated effort by the FDA to review submitted reports for postmarketing requirements and commitments, contributed significantly to the trends reported by the authors. It is also important to understand that pending status does not reflect a delay. Pending investigations are instead proceeding according to the schedule set by the FDA, even if the study has not yet started. The FDA makes concerted efforts to determine the status of postmarketing requirements regularly, assess reasons for any delay, and provide updates to the public. Nearly all
FDAAA postmarketing requirements (99% in 2011) are progressing according to the original schedules set by the FDA. Mwango Kashoki, MD, MPH Cathryn Lee, BSN, MSN, CRNP John Jenkins, MD Author Affiliations: Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland. Corresponding Author: Mwango Kashoki, MD, MPH, Food and Drug Administration, 10903 New Hampshire Ave, WO 22, Room 6464, Silver Spring, MD 20993 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Fain K, Daubresse M, Alexander GC. The Food and Drug Administration Amendments Act and postmarketing commitments. JAMA. 2013;310(2): 202-204. 2. Title IX, subtitle A, §901 of Food and Drug Administration Amendments Act added to the Foods, Drug, and Cosmetic Act (§505[o], 21 USC 355[o]). 3. US Code of Federal Regulations, 21 CFR 314.55(b), 314.510, 314.610(b)(1), 601.27(b), 601.41, and 601.91(b)(1). 4. US Food and Drug Administration. Independent evaluation of FDA’s Prescription Drug User Fee Act—evaluations and initiatives: CDER technical support and analysis. http://www.fda.gov /downloads/Drugs/GuidanceComplianceRegulatoryInformation /Post-marketingPhaseIVCommitments/UCM181135.pdf. Accessed August 7, 2013. 5. US Food and Drug Administration. Report on the review of the backlog of postmarketing requirements and commitments by FDA. http://www .fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation /Post-marketingPhaseIVCommitments/UCM291522.pdf. Accessed August 7, 2013.
In Reply Dr Kashoki and colleagues provide helpful insight about progress made in decreasing the backlog of postmarketing studies from September 2007, when the FDAAA was enacted. Despite this, our research aim was broader: to examine the annual number of postmarketing studies, both required and voluntary, in each status category and the trends since the law’s enactment. The initial backlog of studies is an important part of the picture. However, since September 2007, many new postmarketing studies have been required by the FDA or voluntarily established. The data in the Agency’s Federal Register notices, upon which our analysis relied, include both the backlogged and new studies.1 The revised data cited by the authors, and described in a Congressional report,2 reflect the updated status of the initial backlog of studies as of February 2009, approximately 17 months after FDAAA enactment, but these data do not reflect the status of all postmarketing studies in 2009, or change either our main findings or their substantive interpretation. The estimates by Kashoki and colleagues that approximately 15% of these backlogged studies were delayed in 2009, as well as the Agency’s estimates that 14% of backlogged studies were delayed in 2010,3 are consistent with our estimates that approximately 1 in 8 of all postmarketing studies (241/1781) in 2011 were delayed. This appears to agree with our conclusions about the yearly numbers and trends, particularly that both the number of fulfilled and delayed studies increased during this period.
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